Malaria is a protozoan disease transmitted to mammals, including humans, by the bite of Anopheles mosquitoes. The causative organisms are protozoa of the genus Plasmodium. The sporozoite stage of the parasite lives in the salivary glands of Anopheles mosquitoes from where it is transmitted to mammals.
Four species of Plasmodium are infective to humans. They are P. falciparum, P. vivax, P. ovale and P. malariae. Other species of the parasite are infective in other mammalian species.
Despite years of extensive efforts to eradicate the disease, malaria remains a major worldwide public menace, affecting more than 150,000,000 people in any given year. Combatting malarial infections has become more difficult in recent years due to the spread of drug-resistant parasites (and insecticide-resistant mosquitoes), in many areas. The occurrence of several epidemic outbreaks of this disease lends particular urgency to any efforts designed to combat malaria.
Although the life cycle of Plasmodium is complex, it is well understood in general outline. Nevertheless, much remains to be understood at the biochemical and genetic levels. The organism undergoes distinct morphological changes, involving the participation of a mammalian host and a mosquito vector. Human infection begins when a female mosquito introduces plasmodial sporozoites into the blood system while feeding. After a brief period of time in the peripheral blood, these organisms migrate to the liver. There, they invade hepatocytes where they undergo a morphological change to merozoites and initiate the preclinical exoerythrocytic phase of the disease. By a process of asexual multiplication, a single sporozoite can eventually produce approximately 10.sup.4 hepatic haploid forms termed merozoites. From the liver, the parasite is released to the bloodstream and invades the red blood cells, where it continues its development and asexual multiplication.
International efforts to control or prevent malarial infections in individuals have been only partly successful. Control measures have been directed toward reducing the population levels of the Anopheles mosquito vector, improvement in public health and sanitary procedures, and administration of drugs for both prophylaxis and treatment of individuals at risk.
An alternative approach is based upon the use of monoclonal antibodies capable of inactivating sporozoites, the primary infective agent (Nussenzweig, et al., U.S. Pat. No. 4,466,917; Nussenweig, et al., pending U.S. patent application Ser. No. 574,124). In addition to the foregoing, vaccines are being developed comprising antigenic peptides and proteins derived from the various Plasmodium species (Nussenzweig, et al., U.S. Pat. No. 4,466,917; Nussenzweig, et al., pending U.S. patent application Ser. No. 574,124; Nussenzweig, et al., pending U.S. patent application Ser. No. 574,553; Ellis et al., pending U.S. patent application Ser. No. 633,147; Nussenzweig, et al., pending U.S. patent application Ser. No. 649,903; Schlesinger, et al., pending U.S. patent application Ser. No. 695,257; Nussenzweig, et al., pending U.S. Pat. No. 716,960; and Arnot, et al., pending U.S. patent application Ser. No. 764,645, all incorporated by reference). The use of these materials, directed against the sporozoite stage of the malaria parasite, is capable of providing protection against sporozoite infection in both animals and humans. However, the specific nature of these materials makes it necessary to use immunogens or monoclonal antibodies directed against all of the known Plasmodia which infect humans in order to insure protection from the disease.
The use of appropriate drugs can suppress symptoms in infected individuals living in endemic areas or cure malarial infection completely. Chloroquine and its derivatives have been used successfully in the treatment of malaria. Pyrimethamine, an antifolate agent, has also been effective in the treatment of malaria. Where the drug-resistant forms exist, chloroquine plus pyrimethamine have been used. However, both of these drugs have potential side effects. Chloroquine can induce hemolytic anemia while pyrimethamine can cause megaloblastic anemia. Moreover, as mentioned above, the occurrence of new drug-resistant strains of the malaria parasite has made combatting malarial infestations more difficult.
Interferons are a family of inducible, antiviral proteins and glycoproteins produced by most eukaryotic species in response to a wide variety of viral and non-viral inducers. Three distinct major species of interferons have been characterized and can be distinguished by their physiochemical properties and amino acid sequences, which are quite different. Alpha-interferons are the major species produced by incubating viruses with cells of lymphoid origin. Beta-interferons are the major species produced by nonlymphoid cells upon induction with viral or non-viral agents. Gamma-interferons are the major species produced by lymphocytes (T cells in particular) upon treatment with mitogens, or by sensitized lymphocytes upon treatment with specific antigens. Interferons of all three species are antiviral proteins but also possess other non-antiviral activities of different types and/or in different degrees.
Inducers of alpha- and beta-interferons have been studies for their anti-malarial effect (Jahiel, et al., Nature 220: 710-711, 1968; Jahiel, et al., Science 161: 802-804, 1968). In these articles, statolon, Newcastle disease virus (NDV), and a double-stranded copolymer of polyriboinosinic acid and polyribocytidylic acid (all three now known to induce only alpha- and beta-interferons) were administered to mice before or after infecting the mice with P. berghei sporozoites or with the blood form of this parasite.
The interferon inducers are said to have prolonged the prepatency period to a statistically significant extent, especially which administered within 16-24 hours after sporozoite administration. This effect was much less pronounced against the blood forms of the parasite, or when inducers were administered prior to or later than 24 hours after sporozoite injection. The authors hypothesized--but did not demonstrate--that the protective effect was due to interferon.
It should be noted that interferons manifest a diverse range of antiviral, anticellular and immunoregulatory activities which are dependent upon the specie of interferon employed and the cell type acted upon. It is difficult today (and impossible during the era of the above-cited Jahiel references) to analyze in vivo results and ascribe them to a specific "immunoregulatory", or other, effect of interferon treatment.